Consumer medicine information

Simipex

Pramipexole dihydrochloride monohydrate

BRAND INFORMATION

Brand name

Simipex

Active ingredient

Pramipexole dihydrochloride monohydrate

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Simipex.

SUMMARY CMI

SIMIPEX Tablets

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using SIMIPEX?

SIMIPEX contains the active ingredient Pramipexole dihydrochloride monohydrate.

SIMIPEX is used used in the treatment of Parkinson's disease and Restless Legs Syndrome (RLS).

For more information, see Section 1. Why am I using SIMIPEX? in the full CMI.

2. What should I know before I use SIMIPEX?

Do not use if you have ever had an allergic reaction to SIMIPEX (pramipexole), or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use SIMIPEX? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with SIMIPEX and affect how it works. Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use SIMIPEX?

  • For Parkinson's disease, SIMIPEX 0.125mg tablet should be taken in three times per day. Your daily dose will be increase every week by your doctor until a suitable daily dose is reached.
  • For Restless Legs Syndrome, the usual starting dose is one SIMIPEX 0.125mg tablet once a day, 2 to 3 hours before you go to bed. Your doctor may increase your dose every 4 to 7 days if needed.
  • SIMIPEX tablets should be swallowed whole with a glass of water. SIMIPEX can be taken with or without food.
  • More instructions can be found in Section 4. How do I use SIMIPEX? in the full CMI.

5. What should I know while using SIMIPEX?

Things you should do
  • Tell your doctor if you become pregnant while taking SIMIPEX. Special care is recommended during pregnancy. The benefits of SIMIPEX must be assessed against the possible effects on your unborn child.
Things you should not do
  • Do not take SIMIPEX to treat any other complaint unless your doctor says so.
  • Do not give this medicine to anyone else, even if their symptoms are similar to yours.
Driving or using machines
  • SIMIPEX may cause drowsiness, hallucinations and episodes of sudden onset of sleep, in some people. If affected, do not drive or operate machinery.
Looking after your medicine
  • Keep SIMIPEX Tablets in a cool dry and dark place where the temperature is below 30°C. Keep tablets in the packet until used, to protect from light.

For more information, see Section 5. What should I know while using SIMIPEX? in the full CMI.

6. Are there any side effects?

  • There are a number of side effects associated with this medicine. It is important to be aware of them so that you can identify any symptoms if they occur (see the full CMI for more details). The serious side effects are: loss of memory, fainting, signs of allergy such as rash or hives on the skin, swelling of the face, lips, tongue or other parts of the body, wheezing or difficulty breathing, excessive sleepiness or sudden onset of sleep during normal daily activities, compulsive behaviour such as gambling, hypersexuality, shopping, eating, medication use and repetitive purposeless activities, mental illness causing severe suspiciousness (paranoia), shortness of breath or tightness in the chest. shortness of breath, swelling of the feet or legs due to fluid build-up (heart failure)

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

SIMIPEX Tablets

Active ingredient(s): Pramipexole dihydrochloride monohydrate

Consumer Medicine Information (CMI)

This leaflet provides important information about using SIMIPEX tablets. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist. All medicines have risks and benefits. Your doctor has weighed the risks of you taking SIMIPEX against the benefits this medicine is expected to have for you.

You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using SIMIPEX.

Keep this leaflet with your medicine. You may need to read it again.

Where to find information in this leaflet:

1. Why am I using SIMIPEX?
2. What should I know before I use SIMIPEX?
3. What if I am taking other medicines?
4. How do I use SIMIPEX?
5. What should I know while using SIMIPEX?
6. Are there any side effects?
7. Product details

1. Why am I using SIMIPEX?

SIMIPEX contains the active ingredient Pramipexole dihydrochloride monohydrate. It belongs to a group of medicines known as "dopamine agonists", which bind to dopamine receptors. It is believed that SIMIPEX works by having a similar effect as dopamine in the brain.

SIMIPEX is used in the treatment of Parkinson's disease and Restless Legs Syndrome (RLS).

Parkinson's disease is a disease of the brain that affects body movement.

The symptoms of Parkinson's disease are caused by a lack of dopamine, a naturally occurring chemical produced by certain brain cells. Dopamine relays messages in the part of the brain that controls movement. When too little dopamine is produced, this results in Parkinson's disease. SIMIPEX works by having a similar effect as dopamine in the brain.

Restless Legs Syndrome (RLS)

RLS is a neurological disorder in which there is an overwhelming urge to move the legs to stop unpleasant sensations.

The sensation vary from person to person and range from uncomfortable to irritating to painful. The symptoms usually occur when sitting or lying down - which often leads to problems falling or staying sleep. Sometimes the arms and body may be affected. Current evidence suggests that RLS may be due to faulty dopamine signals in certain areas of the brain. Your doctor may have prescribed SIMIPEX for another reason.

Ask your doctor if you have any questions about why this medicine has been prescribed for you.

SIMIPEX is not addictive.

2. What should I know before I use SIMIPEX?

Warnings

Do not use SIMIPEX if:

  • you are allergic to any medicine containing pramipexole or other or any of the ingredients listed at the end of this leaflet.
  • Always check the ingredients to make sure you can use this medicine.

If you are not sure if you have these allergies, you should raise those concerns with your doctor.

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin

Do not use SIMIPEX if the packaging is torn or shows signs of tampering. Do not use SIMIPEX beyond the expiry date printed on the pack. Return it to your pharmacist for disposal.

Check with your doctor or pharmacist if you:

  • you are not sure whether you should start taking this medicine.

Tell your doctor if you have allergies to any other medicines, or any other substances, such as foods, preservatives or dyes.

It is essential that your doctor knows your medical history before prescribing SIMIPEX. Before taking this medicine. You must tell your doctor if you have, or have had, any of the following conditions:

  • kidney problems
  • mental illnesses
  • low blood pressure
  • trouble controlling your muscles (dyskinesia).

If you are not sure if you have, or have had, any of these conditions, you should raise those concerns with your doctor.

If you have not told your doctor or pharmacist about any of the above, tell them before you start taking or are given SIMIPEX.

Your doctor will advise you whether or not to take SIMIPEX or if you need to adjust the dose or adapt your treatment.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant. Special care is recommended during pregnancy. The benefits of SIMIPEX must be assessed against the possible effects on your unborn child.

SIMIPEX is not recommended during breastfeeding.

Talk to your doctor if you are breastfeeding or intend to breastfeed during your course of medication. In animal studies, SIMIPEX was shown to pass into breast milk, and can stop the production of milk

Use in Children

The use of SIMIPEX is not recommended in child or adolescent below 18 years of age.

Safety and effectiveness in children younger than 18 years have not been established.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may interfere with SIMIPEX and affect how it works.

In particular, you should tell your doctor if you are taking:

Some medicines and SIMIPEX may interfere with each other. These include:

  • levodopa, levodopa/carbidopa combination, or other medicines used to treat Parkinson's disease (e.g. amantadine)
  • medicines used in the treatment of high blood pressure or heart problems (e.g. digoxin, diltiazem, procainamide, quinidine, triamterene, verapamil, hydrochlorothiazide)
  • certain medicines used in the treatment of mental illness/psychosis
  • metoclopramide - commonly used to help control nausea and vomiting
  • cimetidine or ranitidine - used to treat stomach or duodenal ulcer or reflux
  • quinine - used to treat malaria some antibiotics (e.g. trimethoprim, cephalosporins, penicillins)
  • indometacin, a medicine used to treat arthritis
  • chlorpropamide, a medicine used to treat diabetes
  • other medicines that can cause drowsiness or sleepiness (e.g. antihistamine or some cough and cold preparations).

These medicines may be affected by SIMIPEX or may affect how well it works. You may need different amounts of the medicine, or you may need to take different medicines. Your doctor or pharmacist can tell you what to do if you are taking any of these medicines.

4. How do I use SIMIPEX?

How much to take

The dose varies from patient to patient. Your doctor may first start you on a low dose of SIMIPEX and slowly increase the amount of SIMIPEX until the right dose is reached to control your condition.

The tablets should be swallowed whole with a glass of water. SIMIPEX can be taken with or without food.

Parkinson's disease

The recommended initial dose for adults is one SIMIPEX 0.125 mg tablet three times per day. Your daily dose will be increased every week by your doctor until a suitable daily dose is reached.

The maximum recommended daily dose for SIMIPEX is 4.5 mg pramipexole dihydrochloride monohydrate.

Restless Legs Syndrome

The usual starting dose is one SIMIPEX 0.125 mg tablet once a day, usually 2 to 3 hours before you go to bed.

Depending on how you respond to the treatment, your doctor may increase your dose gradually every 4 to 7 days until the right dose for your needs is reached. The maximum dose is 0.75 mg of SIMIPEX per day

Follow all directions given to you by your doctor or pharmacist carefully.

Ask your doctor for more information if you have been advised to take a different dose to that referred to above.

If you do not understand the instructions on the label, ask your doctor or pharmacist for help.

When to take / use SIMIPEX

Take SIMIPEX at about the same time each day.

Taking it at the same time each day will have the best effect. It will also help you remember when to take it

How to take SIMIPEX?

It is important to take your SIMIPEX tablets as directed by your doctor.

A number of tablet strengths are available (see Product description). Make sure that you only take the tablet strength that your doctor has prescribed.

Your doctor may reduce your daily dose if you have another medical condition such as a kidney problem, or if you are currently taking other medicines.

How long to take it

Continue taking SIMIPEX for as long as your doctor tells you. This medicine helps to control your condition but does not cure it. It is important to keep taking your medicine even if you feel well.

If you forget to use SIMIPEX

PARKINSON's DISEASE

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

Otherwise, take it as soon as you remember, then go back to taking it as you would normally.

Do not try to make up for missed doses by taking more than one dose at a time. This may increase the chance of you getting an unwanted side effect.

RESTLESS LEGS SYNDROME

If you forget to take SIMIPEX before you go to bed and you wake up late in the night or early morning, do not take any SIMIPEX as you may have trouble walking in the morning.

Skip the dose you missed and take the next dose when you are meant to.

If you have missed more than one dose, or are not sure what to do, check with your doctor or pharmacist.

If you have trouble remembering when to take your medicine, ask your pharmacist for some hints.

If you use too much SIMIPEX

If you think that you have used too much SIMIPEX, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

Signs of overdose may include nausea, vomiting, abnormal uncontrolled movements, hallucinations, agitation and dizziness or light-headedness.

5. What should I know while using SIMIPEX?

Things you should do

Always follow your doctor's instructions carefully.

Tell your doctor if you become pregnant while taking SIMIPEX.

If you are about to start taking a new medicine, tell your doctor and pharmacist that you are taking SIMIPEX.

Do not stop taking SIMIPEX or change the dose without checking with your doctor. It is important not to suddenly stop taking your SIMIPEX tablets, unless advised to do so by your doctor, since your condition may worsen or you may have unwanted side effects.

If your doctor asks you to stop taking SIMIPEX, the dose will normally need to be reduced gradually over several days.

Tell your doctor as soon as possible if there is any worsening of your condition.

Tell your doctor if, for any reason, you have not used SIMIPEX exactly as prescribed.

Otherwise, your doctor may think that it was not effective and change your treatment unnecessarily.

Seek immediate medical advice if you or your family notices an increase in compulsive behaviour.

Tell your doctor if you experience symptoms such as depression, apathy, anxiety, fatigue, sweating, or pain after stopping or reducing your SIMIPEX treatment. If the problems persist more than a few weeks, your doctor may need to adjust your treatment.

Tell your doctor if you develop an inability to keep your body and neck straight and upright. For example, you may experience abnormal posture such as forward bending of the head and neck, forward bending of the lower back or sidewards bending of the back.

Things you should not do

  • Do not take SIMIPEX to treat any other complaints unless your doctor tells you to.
  • Do not give this medicine to anyone else, even if they have the same condition as you

Driving or using machines

Do not drive a car, operate machinery, or do anything else that could be dangerous (after taking SIMIPEX) until you know how the medicine affects you.

It may cause drowsiness, hallucinations and episodes of sudden onset of sleep, in some people.

Make sure you know how you react to it before you engage in any activities where impaired alertness may put yourself or others at risk of serious injury.

If you experience excessive drowsiness or an episode of sudden onset of sleep (while performing daily activities), do not drive or perform any potentially dangerous activities, and contact your doctor.

Effects of food

Tablets should be taken with or without food

Drinking alcohol

Tell your doctor if you drink alcohol.

Be careful when drinking alcohol while taking SIMIPEX. Combining it and alcohol can make you more drowsy or sleepy.

Be careful getting up from a sitting or lying position. You may feel dizzy or lightheaded while taking SIMIPEX, especially during the first few weeks of treatment. If you wish to stand up, you should do so slowly.

Patients with Parkinson's disease may have an increased risk of developing melanoma.

You should monitor your skin and see your doctor in case of any concerns.

Looking after your medicine

  • Keep SIMIPEX Tablets in the original pack until it is time to take them.
  • Keep SIMIPEX Tablets in a cool dry and dark place where the temperature is below 30°C. Keep tablets in the packet until used, to protect from light.

Do not store your SIMIPEX in direct sunlight or heat. For example, do not leave your SIMIPEX in the car on hot days. Do not store SIMIPEX, or any other medicine, in the bathroom or near a sink.

Do not leave medicines in the car or on window sills. Heat and dampness can destroy some medicines.

Keep your medicines where children cannot reach them. A locked cupboard at least one-and-a-half metres (1.5 m) above the ground is a good place to store medicines.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions.

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking SIMIPEX.

SIMIPEX helps most people with Parkinson's disease but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects. Do not be alarmed by this list of possible side effects. You may not experience any of them.

You should be aware that all prescription medicines carry some risks and that all possible risks may not be known at this stage despite thorough testing.

Your doctor has weighed the risks of your taking SIMIPEX against the expected benefits.

Ask your doctor or pharmacist to answer any questions you may have.

Less serious side effects

Less serious side effectsWhat to do
  • nausea
  • vomiting
  • constipation
  • diarrhoea
  • dry mouth
  • drowsiness
  • tiredness
  • confusion or hallucinations (seeing, feeling or hearing things that are not there)
  • restlessness
  • dizziness
  • headache
  • light-headedness on standing up, especially when getting up from a sitting or lying position (hypotension)
  • blurred vision
  • swelling of hands
  • ankles or feet (peripheral oedema)
  • uncontrollable twitching, jerking or withering movements
  • difficulty sleeping or unusual dreams
  • weight gain or loss
  • loss or gain of sexual drive.
  • Forward bending of the head and neck.
Speak to your doctor or pharmacist if you have any of these less serious side effects and they worry you.

In patients also taking other medicines to treat Parkinson's disease, abnormal uncontrolled movements can occur.

These side effects tend to appear at the start of treatment and lessen or disappear with time.

Sudden onset of sleep episodes (while engaged in daily activities) have been reported with/without prior warning signs, such as excessive drowsiness.

Compulsive behaviour have been reported in patients taking dopamine agonists for the treatment of Parkinson's disease, especially at high doses.

Serious side effects

Serious side effectsWhat to do
  • loss of memory
  • fainting
  • signs of allergy such as rash or hives on the skin, swelling of the face, lips, tongue or other parts of the body, wheezing or difficulty breathing
  • excessive sleepiness or sudden onset of sleep during normal daily activities
  • compulsive behaviour such as gambling, hypersexuality, shopping, eating, medication use and repetitive purposeless activities
  • mental illness causing severe suspiciousness (paranoia)
  • shortness of breath or tightness in the chest.
  • shortness of breath, swelling of the feet or legs due to fluid build-up (heart failure)
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is available with a doctor's prescription.

What SIMIPEX contains

Active ingredient
(main ingredient)		pramipexole dihydrochloride monohydrate
Other ingredients
(inactive ingredients)		SIMIPEX tablets contain:
  • mannitol
  • pregelatinised maize starch
  • microcrystalline cellulose
  • povidone
  • purified talc
  • magnesium stearate
Each SIMIPEX 0.125 mg tablet contains pramipexole dihydrochloride monohydrate 0.125 mg.
Each SIMIPEX 0.25 mg tablet contains pramipexole dihydrochloride monohydrate 0.25 mg.
Each SIMIPEX 1 mg tablet contains pramipexole dihydrochloride monohydrate 1 mg.
Potential allergensNo allergens

Do not take this medicine if you are allergic to any of these ingredients.

What SIMIPEX looks like

SIMIPEX tablets are round and white for each strength.

SIMIPEX 0.125 mg tablets are marked with an “A” on one side of the tablet and are available in blister packs of 30 tablets. (Aust R 172017).

SIMIPEX 0.25 mg tablets are marked with a “B” on one side of the tablet and are available in blister packs of 100 tablets. (Aust R 172018).

SIMIPEX 1 mg tablets are marked with a “D” on one side of the tablet and are available in blister packs of 100 tablets. (Aust R 172021).

SIMIPEX tablets 0.5 (marked with a “C” on one side of the tablet) and 1.5 mg tablets (marked with an “E” on one side of the tablet) are not currently marketed in Australia.

Who distributes SIMIPEX

Arrow Pharma Pty Ltd
15-17 Chapel St
Cremorne VIC 3121
www.arrowpharma.com.au

This leaflet was prepared in December 2022

Published by MIMS March 2023

BRAND INFORMATION

Brand name

Simipex

Active ingredient

Pramipexole dihydrochloride monohydrate

Schedule

S4

 

1 Name of Medicine

Pramipexole dihydrochloride monohydrate.

2 Qualitative and Quantitative Composition

For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Simipex tablets are round and white for each strength.
Simipex 0.125 mg tablets are round, while tablets marked on one side with the letter "A" and plain on the other side..
Simipex 0.25 mg tablets are round, white tablets marked on one side with the letter "B" and scored on the other side.
Simipex 1 mg tablets are round, white tablets marked on one side with the letter "D" and scored on the other side.
Simipex tablets 0.5 (round, white tablets marked on one side with the letter "C" and scored on the other side) and 1.5 mg tablets (round, white tablets marked on one side with the letter "E" and scored on the other side) are not currently marketed in Australia.

4 Clinical Particulars

4.1 Therapeutic Indications

The treatment of signs and symptoms of idiopathic Parkinson's disease. It may be used as monotherapy or in combination with levodopa.
The symptomatic treatment of primary Restless Legs Syndrome.

4.2 Dose and Method of Administration

Parkinson's disease.

The tablets should be taken orally, swallowed with water. The tablets can be taken either with or without food.
The daily dosage is administered in equally divided doses three times/day.

Initial treatment.

Dosages should be increased gradually from a starting dose of pramipexole dihydrochloride monohydrate 0.375 mg/day and then increased every five to seven days. Providing patients do not experience intolerable side effects, the dosage should be titrated to achieve a maximal therapeutic effect. See Table 1.
If a further dose increase is necessary, the daily dose should be increased by 0.75 mg at weekly intervals up to a maximum dose of 4.5 mg/day.

Maintenance treatment.

The individual dose should be in the range of 0.375 mg to a maximum of pramipexole dihydrochloride monohydrate 4.5 mg/day. During dose escalation in three pivotal studies, both in early and advanced disease, efficacy was observed starting at a daily dose of pramipexole dihydrochloride monohydrate 1.5 mg. Further dose adjustments should be done based on the clinical response and tolerability. In clinical trials approximately 5% of patients were treated at doses below 1.5 mg. In advanced Parkinson's disease, doses higher than 1.5 mg/day can be useful in patients where a reduction of the levodopa therapy is intended.

Treatment discontinuation.

Pramipexole dihydrochloride monohydrate should be tapered off at a rate of 0.75 mg per day until the daily dose has been reduced to 0.75 mg. Thereafter the dose should be reduced by 0.375 mg per day. (See Section 4.4 Special Warnings and Precautions for Use).

Dosing in patients with concomitant levodopa therapy.

It is recommended that the dosage of levodopa is reduced during both the dose escalation and the maintenance treatment with pramipexole dihydrochloride monohydrate. Based on clinical trials in advanced patients a reduction of the levodopa dose by 25% or more can be justified. This should be considered also in order to avoid excessive dopaminergic stimulation resulting in dyskinesias, sleep disturbances or hallucinations.

Dosing in patients with renal impairment.

The elimination of pramipexole is dependent on renal function. The following dosage schedule is suggested for initiation of therapy.
Patients with a creatinine clearance above 50 mL/minute require no reduction in daily dose or dosing frequency. In patients with a creatinine clearance between 20 and 50 mL/minute, the initial daily dose of pramipexole dihydrochloride monohydrate should be administered in two divided doses, starting at 0.125 mg twice a day (0.25 mg daily). A maximum daily dose of 2.25 mg should not be exceeded. In patients with a creatinine clearance less than 20 mL/minute, the daily dose of pramipexole dihydrochloride monohydrate should be administered in a single dose, starting at 0.125 mg daily. A maximum daily dose of 1.5 mg should not be exceeded.
If renal function declines during maintenance therapy, reduce pramipexole dihydrochloride monohydrate daily dose by the same percentage as the decline in creatinine clearance, i.e. if creatinine clearance declines by 30%, then reduce the pramipexole dihydrochloride monohydrate daily dose by 30%. The daily dose can be administered in two divided doses if creatinine clearance is between 20 and 50 mL/minute, and as a single daily dose if creatinine clearance is less than 20 mL/minute.

Dosing in patients with hepatic impairment.

Dose adjustment in patients with hepatic failure is probably not necessary, as approximately 90% of absorbed drug is excreted through the kidneys. However, the potential influence of hepatic insufficiency on pramipexole dihydrochloride monohydrate pharmacokinetics has not been investigated.

Restless legs syndrome.

The tablets should be taken orally, swallowed with water. Tablets can be taken either with or without food.
The recommended starting dose is 0.125 mg taken once daily 2 to 3 hours before bedtime. For patients requiring additional symptomatic relief, the dose may be increased every 4 to 7 days to a maximum of 0.75 mg per day. See Table 2.

Treatment discontinuation.

Pramipexole can be discontinued without tapered dose reduction. In a 26 week placebo controlled clinical trial, rebound of RLS symptoms (worsening of symptom severity as compared to baseline) was observed in 10% of patients (14 out of 135) after abrupt discontinuation of pramipexole. This effect was found to be similar across all doses.

Dosing in patients with renal impairment.

The elimination of pramipexole dihydrochloride monohydrate is dependent on renal function and closely related to the creatinine clearance. Based on a pharmacokinetic study in renally impaired subjects, patients with a creatinine clearance above 20 mL/min require no reduction in daily dose. The use of pramipexole dihydrochloride monohydrate in RLS patients with renal impairment has not been studied.

Dosing in patients with hepatic impairment.

Dose reduction is not considered necessary in patients with hepatic impairment, as approximately 90% of absorbed drug is excreted through the kidneys.

Dosing in children and adolescents.

Safety and efficacy of pramipexole dihydrochloride monohydrate have not been established in children and adolescents below 18 years.

4.3 Contraindications

Hypersensitivity to pramipexole or any excipients of Simipex.

4.4 Special Warnings and Precautions for Use

Somnolence and sudden onset of sleep.

Pramipexole has been associated with somnolence and episodes of sudden sleep onset, particularly in patients with Parkinson's disease. Sudden onset of sleep during daily activities, in some cases without awareness or warning signs such as excessive drowsiness, has been reported. Some of these events have been reported as late as one year after the initiation of treatment. Before initiating treatment with pramipexole, patients should be advised of the potential to develop drowsiness and specifically asked about factors that may increase the risk with pramipexole, such as concomitant sedation medications, the presence of sleep disorders and concomitant medications that increase pramipexole plasma levels (e.g. cimetidine).
Patients must be informed of the potential sedating effects associated with pramipexole, including somnolence and the possibility of falling asleep while engaged in activities of daily living. Since somnolence is a frequent adverse event with potentially serious consequences, patients should neither drive a car nor operate other complex machinery until they have gained sufficient experience with pramipexole to gauge whether or not it affects their mental and/or motor performance adversely. Many clinical experts believe that falling asleep while engaged in activities of daily living always occurs in a setting of pre-existing somnolence, although patients may not give such a history. For this reason, prescribers should continually reassess patients for drowsiness or sleepiness, especially since some of these events occur well after the start of treatment.
Prescribers should also be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities. Patients should be advised that if increased somnolence or episodes of falling asleep during activities of daily living (e.g. conversations, eating) are experienced at any time during treatment, they should not drive or participate in potentially dangerous activities and should contact their doctor. Furthermore, a reduction of dosage or termination of therapy may be considered. While dose reduction clearly reduces the degree of somnolence, there is insufficient information to establish that dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living. Patients must also be advised to exercise caution when taking other sedating medication or alcohol in combination with pramipexole because of possible additive somnolent effects.

Renal impairment.

When prescribing Simipex in a patient with renal impairment a reduced dose is suggested (see Section 4.2 Dose and Method of Administration).

Hallucinations and confusion.

Hallucinations and confusion are known side effects of treatment with dopamine agonists and levodopa in Parkinson's disease patients. Hallucinations were more frequent when pramipexole was given in combination with levodopa in Parkinson's disease patients with advanced disease than monotherapy in patients with early disease. Within the clinical development program for registration of the Restless Legs Syndrome indication, one case of hallucinations has been reported. Patients should be informed that hallucinations (mostly visual) can occur and may adversely affect their ability to drive.

Dyskinesias.

In advanced Parkinson's disease, in combination treatment with levodopa, dyskinesias can occur during the initial titration of pramipexole. If dyskinesias occur, the dose of levodopa should be decreased.

Patients with psychotic disorders.

Patients with psychotic disorders should only be treated with a dopamine agonist if the potential benefits outweigh the risks. Co-administration of antipsychotic medicinal products with pramipexole is not recommended, e.g. if dopamine-antagonistic effects can be expected.

Postural hypotension.

In case of severe cardiovascular disease, care should be taken. It is recommended to monitor blood pressure, especially at the beginning of treatment, due to the general risk of postural hypotension associated with dopaminergic therapy.

Dystonia.

Patients with Parkinson's disease may be present with axial dystonia such as antecollis, camptocormia or pleurothotonus (Pisa Syndrome). Dystonia has been reported following initiation of dopamine agonists including pramipexole. Dystonia may also occur several months following medication initiation or adjustments. If dystonia occurs, the dopaminergic medication regimen should be reviewed and an adjustment considered.

Retinal changes.

Animal studies.

Long-term treatment of albino rats with pramipexole resulted in retinal degeneration, characterised by loss of photoreceptor cells. In short-term studies, this was also produced in albino rats by continuous exposure to light, and was potentiated by pramipexole. Similar changes were not induced by higher intensity continuous light exposure in pigmented rats, with or without pramipexole treatment. Pramipexole has been shown to inhibit the naturally occurring photoreceptor cell disk shedding process in albino rats.

Human studies.

The long-term ophthalmic safety of pramipexole in patients with Parkinson's disease was assessed in an open label cross sectional, assessor blinded, matched pair design study. The average treatment duration was approximately four years and exceeded 2.5 years in all patients. This study showed that there was no evidence that prolonged treatment with pramipexole induced more signs of retinal degeneration in patients with Parkinson's disease than other dopamine agonists.

Fibro-osseous proliferative lesions in mice.

An increased incidence of fibro-osseous proliferative lesions occurred in the femurs of female mice treated for two years with pramipexole at doses 0.5 times the highest clinical dose (based on body surface area) and above. Similar lesions were not observed in male mice or rats and monkeys of either sex that were treated chronically with pramipexole. The potential significance in humans is not known.

Rhabdomyolysis.

A single case of rhabdomyolysis occurred in a patient with advanced Parkinson's disease treated with pramipexole. The patient was hospitalised with an elevated creatine phosphokinase (CPK). The symptoms resolved with discontinuation of the medication.

Events reported with dopaminergic therapy.

Although the events enumerated below have not been reported in association with the use of pramipexole in the development program, they are associated with the use of other dopaminergic drugs. The expected incidence of these events, however, is so low that even if pramipexole caused these events at rates similar to those attributable to other dopaminergic therapies, it would be unlikely that even a single case would have occurred in a cohort of the size exposed to pramipexole in studies to date.
In patients with Parkinson's disease there are uncertain results regarding a potential increased risk of developing melanoma.
Patients and their doctors should be aware of this potential additional risk for developing melanoma, and monitor their skin accordingly.

Withdrawal emergent hyperpyrexia and confusion.

Although not reported with pramipexole in the development program, a symptom complex resembling the neuroleptic malignant syndrome (characterised by elevated temperature, muscular rigidity, altered consciousness and autonomic instability), with no other obvious aetiology, has been reported in association with rapid dose reduction, withdrawal of or changes in antiparkinsonian therapy. (See Section 4.2 Dose and Method of Administration).

Fibrotic complications.

Although not reported with pramipexole in the development program, cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion and pleural thickening have been reported in some patients treated with ergot derived dopaminergic agents. While these complications may resolve when the drug is discontinued, complete resolution does not always occur.
Although these adverse events are believed to be related to the ergoline structure of these compounds, whether other, nonergot derived dopamine agonists (such as pramipexole) can cause them is unknown.

Compulsive behaviour.

Compulsive behaviour such as gambling, hypersexuality, shopping, eating, medication use and punding (repetitive purposeless activity) has been reported in patients taking dopamine agonists for the treatment of Parkinson's disease, especially at high doses. Prescribers, patients and caregivers should be alert to the possibility of such behaviour, which may have serious financial and social consequences.
Dose reduction/ taper discontinuation should be considered.

Augmentation in restless legs syndrome (RLS).

Reports in the literature indicate that treatment of RLS with dopaminergic medications can result in augmentation. Augmentation refers to the earlier onset of symptoms in the evening (or even the afternoon), increase in symptoms, and spread of symptoms to involve other extremities. Augmentation was specifically investigated in a controlled clinical trial over 26 weeks. Kaplan-Meier analysis of time to augmentation showed no statistically significant difference between pramipexole (N = 152) and placebo groups (N = 149). The frequency and severity of augmentation after longer-term use of pramipexole and the appropriate management of these events have not been adequately evaluated in controlled clinical trials.

Treatment discontinuation for RLS.

In RLS clinical trials, some patients have reported worsening of the RLS symptoms following abrupt discontinuation of pramipexole treatment. The worsening of symptoms was independent of pramipexole dihydrochloride monohydrate dosage and generally resolved within one week. For the RLS treatment, pramipexole can be discontinued without tapered dose reduction.

Drug withdrawal syndrome.

A drug withdrawal syndrome has been reported during or after discontinuation of dopamine agonists including pramipexole. Risk factors may include high cumulative dopaminergic exposure. Withdrawal symptoms including apathy, anxiety, depression, fatigue, sweating and pain may occur when tapering or discontinuing dopamine agonists, including pramipexole and may be severe (see Section 4.8 Adverse Effects (Undesirable Effects)). Withdrawal symptoms do not respond to levodopa. To discontinue treatment in patients with Parkinson's disease, pramipexole should be tapered off (see Section 4.2 Dose and Method of Administration).
Patients should be informed about potential drug withdrawal symptoms before tapering pramipexole and closely monitored during and after discontinuation. In case of persistent or severe withdrawal symptoms, it may be necessary to temporarily re-administer or increase a dopamine agonist at the lowest effective dose.

Use in the elderly.

When prescribing Simipex, age related reduction in renal function, which can result in a decline in renal clearance, should be considered, as this may cause an increase in the elimination half-life of pramipexole dihydrochloride monohydrate.
There are no apparent differences in the efficacy or safety between older and younger patients, except the relative risk of hallucination associated with the use of pramipexole was increased in the elderly.

Paediatric use.

The safety and efficacy of pramipexole in children have not been established.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Pramipexole is bound to plasma proteins to a very low extent (about 15%) and little biotransformation is seen in humans. Therefore, metabolic interactions with other medications affecting plasma protein binding or elimination by biotransformation are unlikely.
The toxicological consequences (long-term, reproduction, carcinogenicity/ mutagenicity) of using pramipexole in combination with other Parkinson's disease medications have not been evaluated in animals.

CYP interactions.

Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolised by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYP1A2, CYP2C9, CYP2C19, CYP2E1 and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 microM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid).

Anticholinergics.

As anticholinergics are mainly eliminated by biotransformation, the potential for an interaction is limited, although an interaction with anticholinergics has not been investigated.

Carbidopa/ levodopa.

Carbidopa/ levodopa did not influence the pharmacokinetics of pramipexole in healthy volunteers (n = 10). Pramipexole did not alter the extent of absorption (AUC) or the elimination of carbidopa/ levodopa, although it caused an increase in levodopa Cmax by about 40% and a decrease in Tmax from 2.5 to 0.5 hours. When pramipexole dihydrochloride monohydrate is given in combination with levodopa, it is recommended that the dosage of levodopa is reduced and the dosage of other antiparkinsonian medication is kept constant while increasing the dose of pramipexole dihydrochloride monohydrate.

Selegiline.

In healthy volunteers (n = 11), selegiline did not influence the pharmacokinetics of pramipexole.

Antipsychotic medicinal products.

Co-administration of antipsychotic medicinal products with pramipexole is not recommended, e.g. if dopamine-antagonistic effects can be expected (see Section 4.4 Special Warnings and Precautions for Use).

Drugs eliminated via renal secretion and renal tubular secretion inhibitors.

Drugs that inhibit the active renal tubular secretion of basic (cationic) drugs or are eliminated by this pathway may interact with pramipexole, resulting in reduced clearance of either or both drugs. Drugs included in this category are cimetidine, diltiazem, quinidine, quinine, ranitidine, triamterene, verapamil, digoxin, procainamide and trimethoprim. Amantadine is also eliminated by this renal pathway. In case of concomitant treatment with this type of drug, attention should be paid to signs of dopamine overstimulation, such as dyskinesias, agitation or hallucinations. Reduction of the pramipexole dose should be considered when these drugs are administered concomitantly with pramipexole.
Drugs secreted by the anionic transport system (e.g. cephalosporins, penicillins, indometacin, hydrochlorothiazide and chlorpropamide) are likely to have little effect on the clearance of pramipexole. Probenecid, a known inhibitor of renal tubular secretion of organic acids via the anionic transporter, did not noticeably influence pramipexole pharmacokinetics (n = 12).

Alcohol and other sedating medications.

Because of possible additive effects, caution should be advised when patients are taking alcohol or other sedating medications in combination with pramipexole and when taking concomitant medicines that increase plasma levels of pramipexole.

Dopamine antagonists.

Since pramipexole is a dopamine agonist, dopamine antagonists such as the neuroleptics (phenothiazines, butyrophenones, thioxanthines) or metoclopramide may diminish the effectiveness of pramipexole and should not be administered concurrently.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

In rat fertility studies, doses of 2.5 mg/kg/day (approximately five times human exposure at the maximum recommended clinical dose of 4.5 mg/day, based on AUC) pramipexole prolonged oestrus cycles and inhibited nidation. These effects were associated with reductions of serum prolactin, a hormone necessary for implantation and maintenance of pregnancy in rats. Treatment of male rats with pramipexole had no effect on fertility. The effects of pramipexole on the fertility of a species in which implantation and maintenance of early pregnancy is not dependent on prolactin have not been investigated.
No studies on the effect on human fertility have been conducted.
(Category B3)
The potential effects of pramipexole on reproductive function have been investigated in rats and rabbits. Pramipexole was not teratogenic in rats and rabbits but was embryotoxic in the rat at maternotoxic doses.
Administration of pramipexole 0.1, 0.5 or 1.5 mg/kg (approximately 0.3, 1.7 and 5 times human exposure at the maximum recommended human dose of 1.5 mg tid and based on area under the curve (AUC)) to pregnant rats during the period of organogenesis resulted in a high incidence of total resorption of embryos at 1.5 mg/kg. No teratogenic effects were observed, however, because of the pregnancy impairment and embryolethality, limited teratogenicity data from the highest test dose were obtained. These finding are thought to be due to the prolactin lowering effect of pramipexole, since prolactin is necessary for implantation and maintenance of early pregnancy in rats (but not in rabbits or humans). Administration of oral doses of up to 10 mg/kg/day to rabbits during organogenesis (approximately 80 times human exposure at the maximum recommended human dose, 1.5 mg tid and based on AUC) did not result in any embryotoxic, fetotoxic or teratogenic effects.
Postnatal growth was inhibited in the offspring of rats treated with 0.5 mg/kg/day or greater during the latter part of pregnancy and throughout lactation (the plasma AUC was 1.7 times the AUC in humans dosed at 1.5 mg tid).
There are no adequate and well controlled studies in pregnant women. Pramipexole should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.
 The effect on lactation has not been investigated in humans. As pramipexole treatment inhibits secretion of prolactin in humans, inhibition of lactation is expected. The excretion of pramipexole into breast milk has not been studied in women. In rats, the concentration of drug related material was higher in breast milk than in plasma. In the absence of human data, pramipexole should not be used during breastfeeding, if possible. However, if its use is unavoidable, breastfeeding should be discontinued.

4.7 Effects on Ability to Drive and Use Machines

Patients should be informed that hallucinations can occur and may adversely affect their ability to drive. Also, they should be alerted to the potential sedating effects associated with pramipexole, including somnolence and the possibility of falling asleep while engaged in activities of daily living.
Since somnolence is a frequent adverse event with potentially serious consequences, patients should neither drive a car nor operate other complex machinery until they have gained sufficient experience with pramipexole to gauge whether or not it affects their mental and/or motor performance adversely. Patients should be advised that if increased somnolence or episodes of falling asleep during activities of daily living (e.g. conversations, eating) are experienced at any time during treatment, they should not drive or participate in potentially dangerous activities and should contact their doctor.

4.8 Adverse Effects (Undesirable Effects)

Parkinson's disease clinical trials.

The following adverse events have been reported more frequently during the use of pramipexole than under placebo: nausea, constipation, somnolence, hallucinations, confusion, dizziness and peripheral oedema. More frequent adverse reactions in early disease were somnolence and constipation, and in advanced disease and in combination with levodopa treatment, dyskinesia and hallucinations. These adverse events decreased with continued therapy; constipation, nausea and dyskinesia tended to even disappear.
Falling asleep while engaged in activities of daily living has been reported in patients with or without the perception of prior warning signs, such as excessive drowsiness.
The incidence of hypotension under pramipexole, compared to placebo treatment, was not increased. However, in individual patients, hypotension may occur at the beginning of treatment, especially if pramipexole is titrated too rapidly.
A summary of adverse events reported in 1% or more of Parkinson's disease patients in controlled clinical studies is presented in Table 3.
Other events reported by 1% or more of patients treated with pramipexole but reported equally or more frequently in the placebo group were as follows.
Early Parkinson's disease. Infection, accidental injury, headache, pain, tremor, back pain, syncope, postural hypotension, hypertonia, diarrhoea, rash, ataxia, dry mouth, leg cramps, twitching, pharyngitis, sinusitis, sweating, rhinitis, urinary tract infection, vasodilation, flu syndrome, increased saliva, tooth disease, dyspnoea, increased cough, gait abnormalities, urinary frequency, vomiting, allergic reaction, hypertension, pruritus, hypokinesia, increased CPK, nervousness, dream abnormalities, chest pain, neck pain, paraesthesia, tachycardia, vertigo, voice alteration, conjunctivitis, paralysis, accommodation abnormalities, tinnitus, diplopia and taste perversions.
Advanced Parkinson's disease. Nausea, pain, infection, headache, depression, tremor, hypokinesia, anorexia, back pain, dyspepsia, flatulence, ataxia, flu syndrome, sinusitis, diarrhoea, myalgia, abdominal pain, anxiety, rash, paraesthesia, hypertension, increased saliva, tooth disorder, apathy, hypotension, sweating, vasodilation, vomiting, increased cough, nervousness, pruritus, hyperaesthesia, neck pain, syncope, arthralgia, dysphagia, palpitations, pharyngitis, vertigo, leg cramps, conjunctivitis and lacrimation disorders.
The events listed below occurred in less than 1% of patients exposed to pramipexole during premarketing development. All reported events, except those already listed above, are included without regard to determination of a causal relationship to pramipexole. Events are listed within the body system categories in order of decreasing frequency.

Body as a whole.

Fever, enlarged abdomen, rigid neck, no drug effect.

Cardiovascular system.

Palpitations, angina pectoris, atrial arrhythmia, peripheral vascular disease.

Digestive system.

Tongue discolouration, gastrointestinal (GI) haemorrhage, faecal incontinence.

Endocrine system.

Diabetes mellitus.

Haemic and lymphatic system.

Ecchymosis.

Metabolic and nutritional system.

Gout.

Musculoskeletal system.

Bursitis, myasthenia.

Nervous system.

Apathy, libido decrease, paranoid reaction, akinesia, coordination abnormalities, speech disorder, hyperkinesia, neuralgia.

Respiratory system.

Voice alteration, asthma, haemoptysis.

Skin and appendages.

Skin disorder, herpes simplex.

Special senses.

Tinnitus, taste perversion, otitis media, dry eye, ear disorder, hemianopia.

Urogenital system.

Urinary incontinence, dysuria, prostate disorder, kidney calculus.
The safety profile of the immediate-release pramipexole tablets and the extended-release pramipexole ER tablets was comparable, in both the early and advanced Parkinson's disease clinical studies, at comparable daily doses and duration of treatment.

Restless legs syndrome clinical trials.

In the treatment of RLS, pramipexole has been evaluated for safety in 889 patients, including 427 treated for over six months and 75 for over one year. The overall safety assessment focuses on the results of three double-blind, placebo-controlled trials, in which 575 patients with RLS were treated with pramipexole for up to 12 weeks. The most commonly observed adverse events with pramipexole in the treatment of RLS (observed in > 5% of pramipexole treated patients and at a rate at least twice that observed in placebo-treated patients) were nausea and somnolence. Occurrences of nausea and somnolence in clinical trials were generally mild and transient.
Approximately 7% of 575 patients treated with pramipexole during the double-blind periods of three placebo-controlled trials discontinued treatment due to adverse events compared to 5% of 223 patients who received placebo. The adverse event most commonly causing discontinuation of treatment was nausea (1%).
A summary of adverse events reported in 1% or more of RLS patients in controlled clinical studies is presented in Table 4.
In general, the prevalence of nausea and fatigue was reduced with continued pramipexole therapy.
Adverse reactions reported in less than 1% of 575 patients treated with pramipexole (and numerically more frequent than in the placebo group) in the controlled studies are listed by system organ class below.

Blood and lymphatic system disorders.

Leukopenia.

Cardiac disorders.

Palpitations.

Ear and labyrinth disorders.

Deafness, tinnitus.

Eye disorders.

Abnormal sensation in eye, diplopia, eye oedema, vision blurred, visual impairment.

Gastrointestinal disorders.

Abdominal distension, abdominal pain, gastritis, GI pain, intestinal spasm, salivary hypersecretion, stomach discomfort.

General disorders and administration site conditions.

Chest pain, feeling abnormal, feeling drunk, irritability, pitting oedema.

Investigations.

Blood triglycerides increased, body temperature increased, heart rate increased, lipase increased, weight increased.

Metabolism and nutrition disorders.

Increased appetite.

Musculoskeletal and connective tissue disorders.

Joint stiffness, muscle tightness.

Nervous system disorders.

Postural dizziness, dysgeusia, lethargy, loss of consciousness, sedation, syncope, tremor.

Psychiatric disorders.

Agitation, cognitive deterioration, confusional state, disorientation, dysphoria, excitability, flight of ideas, initial insomnia, libido decreased, middle insomnia, restlessness, sleep disorder.

Renal and urinary disorders.

Nocturia, pollakiuria.

Reproductive system and breast disorders.

Breast discomfort.

Respiratory, thoracic and mediastinal disorders.

Hiccups, nasal disorder, pharyngeal oedema, yawning.

Skin and subcutaneous system disorders.

Night sweats, purpura, rash, skin hyperpigmentation.

Vascular disorders.

Hot flush, hypertension.

Postmarketing experience.

In addition to the adverse events reported during clinical trials, the following adverse reactions have been identified (essentially in Parkinson's disease patients) during post-approval use of pramipexole. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: abnormal dreams, amnesia, antecollis, cardiac failure, accidents (including fall), blackouts, fatigue, hallucinations, headache, hiccups, hypotension (including postural hypotension), inappropriate antidiuretic hormone secretion, increased eating (including binge eating, compulsive eating and hyperphagia), libido disorders (including increased and decreased libido), hypersexuality, compulsive shopping and other abnormal behaviour; (reflecting symptoms of impulse control disorders and compulsions) restlessness, paranoia, syncope, visual disturbance including blurred vision and reduced visual acuity, vomiting, weight decrease including decreased appetite, weight increase, pneumonia, dyspnoea and hypersensitivity.
Pramipexole may also be associated with disorders of libido (increased or decreased).
Patients treated with pramipexole have rarely reported suddenly falling asleep (or sudden onset of sleep) while engaged in activities of daily living, including operation of motor vehicles which has sometimes resulted in accidents (see Section 4.4 Special Warnings and Precautions for Use). Some of them did not report a warning sign such as somnolence, which is a common occurrence in patients receiving pramipexole, and which, according to the current knowledge of sleep physiology, always proceeds falling asleep. There was no clear relation to the duration of treatment. Some patients were taking other medication with potentially sedative properties. In most cases where information was available, there were no further episodes following reduction of dosage or termination of therapy.
Patients treated with dopamine agonists for Parkinson's disease, including pramipexole, especially at high doses, have been reported as exhibiting signs of pathological gambling, increased libido and hypersexuality, generally reversible upon reduction of the dose or treatment discontinuation.
In clinical studies and postmarketing experience cardiac failure has been reported in patients with pramipexole. In a pharmacoepidemiological study pramipexole use was associated with an increased risk of cardiac failure compared with nonuse of pramipexole.

Drug withdrawal syndrome (dopamine agonist withdrawal syndrome).

Withdrawal symptoms including apathy, anxiety, depression, fatigue, sweating and pain may occur when tapering or discontinuing dopamine agonists, which may be severe (see Section 4.4 Special Warnings and Precautions for Use).

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at http://www.tga.gov.au/reporting-problems.

4.9 Overdose

For information on the management of overdose, contact Poisons Information Centre on 13 11 26 (Australia).

Symptoms.

There is no clinical experience with massive overdosage. The expected adverse events should be those related to the pharmacodynamic profile of a dopamine agonist, including nausea, vomiting, hyperkinesia, hallucinations, agitation and hypotension.

Treatment.

There is no established antidote for overdosage of a dopamine agonist. If signs of central nervous system stimulation are present, a neuroleptic agent may be indicated. Management of the overdose may require general supportive measures, intravenous fluids and electrocardiogram monitoring.
Haemodialysis has not been shown to be helpful.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Pharmacotherapeutic group: dopamine agonist, ATC code: N04BC05.
Pramipexole is a dopamine agonist that binds with high selectivity and specificity to the dopamine D2 subfamily receptors and has a preferential affinity to D3 receptors. It has full intrinsic activity.
Pramipexole alleviates Parkinsonian motor deficits by stimulation of dopamine receptors in the striatum. Animal studies have shown that pramipexole inhibits dopamine synthesis, release and turnover.
The precise mechanism of action of pramipexole as a treatment for Restless Legs Syndrome is not known. Although the pathophysiology of Restless Legs Syndrome is largely unknown, neuropharmacological evidence suggests primary dopaminergic system involvement.
Positron emission tomographic (PET) studies suggest that a mild striatal presynaptic dopaminergic dysfunction may be involved in the pathogenesis of Restless Legs Syndrome. In human volunteers a dose dependent decrease in prolactin was observed.

Clinical trials.

Parkinson's disease.

The clinical program for pramipexole dihydrochloride monohydrate was designed to evaluate its efficacy in the treatment of both early and advanced Parkinson's disease.
In all studies, the Unified Parkinson's Disease Rating Scale (UPDRS), or one or more of its subparts, served as the primary outcome assessment measure. The UPDRS is a four part multi-item rating scale intended to evaluate mentation (part I), activities of daily living (part II), motor performance (part III) and complications of therapy (part IV).
Part II of the UPDRS contains 13 questions related to activities of daily living, which are scored from 0 (normal) to 4 (maximal severity) for a maximum (worst) score of 52. Part III of the UPDRS contains 14 items designed to assess the severity of the cardinal motor findings in patients with Parkinson's disease (e.g. tremor, rigidity, bradykinesia, postural instability, etc.), scored for different body regions and has a maximum (worst) score of 108.
The Hoehn and Yahr scale is used to rate the severity of Parkinson's disease, and has six stages - stage 0 (no signs of disease) to stage V (wheelchair bound or bedridden unless aided).
Studies in patients with early Parkinson's disease. Patients evaluated in these studies were diagnosed with idiopathic Parkinson's disease, characterised by Hoehn and Yahr stage I to III. In two studies (protocols M/2730/0005 and M/2730/0072) the presence of two cardinal symptoms (resting tremor, bradykinesia or rigidity) was required. In trials M/2730/0004 and M/2730/0072 the duration of Parkinson's disease was limited to seven years.
One study (M/2730/0001, n = 335) was a double blind, placebo controlled, parallel trial consisting of a seven-week dose escalation period and a six-month maintenance period. Patients could be on selegiline, anticholinergics or both, but could not be on levodopa products or amantadine. Patients were randomised to pramipexole dihydrochloride monohydrate or placebo. Patients treated with pramipexole dihydrochloride monohydrate had a starting dose of 0.375 mg and were titrated to a maximally tolerated dose, but no higher than 4.5 mg/day in three divided doses. At the end of the six-month maintenance period, the mean improvement from baseline on the UPDRS part II total score was 1.9 in the group receiving pramipexole dihydrochloride monohydrate and -0.4 in the placebo group, a difference that was statistically significant (p less than or equal to 0.0001). The mean improvement from baseline on the UPDRS part III total score was 5.0 in the group receiving pramipexole dihydrochloride monohydrate and -0.8 in the placebo group, a difference that was also statistically significant (p less than or equal to 0.0001). A statistically significant difference between groups in favour of pramipexole dihydrochloride monohydrate was seen beginning at week 2 of the UPDRS part II (maximum dose 0.75 mg/day) and at week 3 of the UPDRS part III (maximum dose 1.5 mg/day).
The second study (M/2730/0004, n = 264) was a double blind, placebo controlled, parallel trial consisting of a six-week dose escalation period and a four-week maintenance period. Patients could be on selegiline, anticholinergics, amantadine or any combination of these, but could not be on levodopa products. Patients were randomised to one of four fixed doses of pramipexole dihydrochloride monohydrate (1.5, 3.0, 4.5 or 6.0 mg/day) or placebo. At the end of the four-week maintenance period, the mean improvement from baseline on the UPDRS part II total score was 1.8 in the patients treated with pramipexole dihydrochloride monohydrate, regardless of dose, and 0.3 in placebo treated patients. The mean improvement from baseline on the UPDRS part III total score was 4.2 in patients treated with pramipexole dihydrochloride monohydrate and 0.6 in placebo treated patients. No dose response relationship was demonstrated. The between treatment differences on both parts of the UPDRS were statistically significant in favour of pramipexole dihydrochloride monohydrate for all doses.
The third study (M/2730/0005, n = 290) was a double blind, placebo controlled, parallel design consisting of a seven-week dose escalation period and a 24-week maintenance period (same as M/2730/0001). Again, patients were allowed use of selegiline, anticholinergics, amantadine or any combination of these, but not levodopa products. Patients treated with pramipexole dihydrochloride monohydrate had a starting dose of 0.375 mg/day and were titrated to a maximally tolerated dose, but no higher than 4.5 mg/day. Pramipexole dihydrochloride monohydrate significantly (p less than or equal to 0.0022) reduced the severity of disease as measured by a decrease in the primary efficacy endpoints (change from baseline to the last visit prior to dose reduction) of both parts II and III of the UPDRS. This significant difference (p less than or equal to 0.021 for UPDRS parts II and III) was also seen at maintenance weeks 8, 12 and 16. Based on their steadily decreasing UPDRS total scores for parts II and III, patients on pramipexole dihydrochloride monohydrate exhibited clinical improvement throughout treatment.
There was a further study (M/2730/0072, n = 301) which was a double blind, parallel design comparison of pramipexole dihydrochloride monohydrate and carbidopa/ levodopa for initial treatment in early symptomatic Parkinson's disease. The primary objective was to compare the treatments with regard to the development of dopaminergic motor complications. Results for the first two years (as described in the original protocol) are available. The efficacy results showed that initial treatment with pramipexole dihydrochloride monohydrate was superior to carbidopa/ levodopa, as measured by the amount of time elapsed before the first occurrence of dopaminergic complications. At the end of the maintenance interval, fewer patients treated with pramipexole dihydrochloride monohydrate (27.8%) than carbidopa/ levodopa (50.7%) experienced dopaminergic motor complications (wearing off, 'on' and 'off' fluctuations, and dyskinesias). Similar results were obtained when the occurrence of each dopaminergic motor complication was analysed separately. The incidence of other dopaminergic complications (freezing, confusion, hallucinations and dementia) were similar in both groups, with only hallucinations occurring more frequently in the pramipexole dihydrochloride monohydrate group (9.3%) than the carbidopa/ levodopa group (3.3%). At the end of the maintenance interval (23.5 months), the mean total change of the UPDRS score for the pramipexole dihydrochloride monohydrate and carbidopa/ levodopa groups were -4.7 and -9.3, respectively. The results show that pramipexole is more effective than carbidopa/ levodopa in delaying the occurrence of dopaminergic motor complications. Monotherapy with pramipexole is effective in the treatment of patients with early Parkinson's disease and in the delay of motor complications. Long-term administration of pramipexole was well tolerated and the adverse event profile was consistent with that reported for other pramipexole and levodopa trials.
Studies in patients with advanced Parkinson's disease.

Pramipexole tablets.

Patients in these studies were in an advanced stage of disease (Hoehn and Yahr stage II to IV) during 'on' periods. Patients in the first study (M/2730/0010, n = 360) had a mean disease duration of nine years, had been exposed to levodopa for long periods of time (mean eight years), used concomitant levodopa during the trial and had 'on-off' periods. The study was a double blind, placebo controlled, parallel trial consisting of a seven-week dose escalation period and a six-month maintenance period. Patients were treated with concomitant levodopa products and could additionally be on concomitant selegiline, anticholinergics, amantadine or any combination. Patients treated with pramipexole dihydrochloride monohydrate had a starting dose of 0.375 mg/day and were titrated to a maximally tolerated dose, but no higher than 4.5 mg/day in three divided doses. At selected times during the six-month maintenance period, patients were asked to record the amount of 'off', 'on' or 'on with dyskinesia' time/day for several sequential days. At the end of the six-month maintenance period, the mean improvement from baseline on the UPDRS part II total score was 2.7 in the group treated with pramipexole dihydrochloride monohydrate and 0.5 in the placebo group, a difference that was statistically significant (p less than or equal to 0.01). The mean improvement from baseline on the UPDRS part III total score was 5.6 in the group treated with pramipexole dihydrochloride monohydrate and 2.8 in the placebo group, a difference that was statistically significant (p less than or equal to 0.01). A statistically significant difference between groups in favour of pramipexole dihydrochloride monohydrate was seen at week 3 of the UPDRS part II (maximum dose 0.75 mg/day) and at week 2 of the UPDRS part III (maximum dose 1.5 mg/day). Dose reduction of levodopa was allowed during this study if dyskinesia (or hallucinations) developed; levodopa dosage reduction occurred in 76% of patients treated with pramipexole versus 54% of placebo patients. On average, the levodopa dose was reduced by 27%. The mean number of 'off' hours/day during baseline was six hours for both treatment groups. Throughout the trial, patients treated with pramipexole had a mean of four 'off' hours/day, while placebo treated patients continued to experience six 'off' hours/day.
The second study (M/2730/0036, n = 247) was a double blind, placebo controlled, parallel trial consisting of a 12-week titration, six-month maintenance and one week dose reduction period. Pramipexole dihydrochloride monohydrate and bromocriptine were used as adjunctive treatment to levodopa. Patients with disturbances continuing individually optimised levodopa therapy were included. Primary endpoints were the UPDRS parts II and III. At the end of the maintenance period, the median changes from baseline on the UPDRS part II for pramipexole dihydrochloride monohydrochloride and placebo were -2.5 and -0.5, respectively (p = 0.0002). In the UPDRS part III, the changes for pramipexole dihydrochloride monohydrate and placebo were -6.0 and -2.0, respectively (p = 0.0006). Pramipexole dihydrochloride monohydrate was superior to placebo for UPDRS parts II and III from four and six weeks on, respectively. Superiority of pramipexole dihydrochloride monohydrate over placebo was also shown for UPDRS part II during 'on' periods. In the pramipexole dihydrochloride monohydrate group average percentage of 'off' time decreased by 15.4% and in the placebo group by 2.3%. A reduction of 15% is approximately equal to a reduction of 2.5 hours/day, an important clinical improvement. Both pramipexole dihydrochloride monohydrate and bromocriptine were superior to placebo with respect to the primary endpoints (UPDRS parts II and III). For percentage of 'off' time and global assessment of efficacy pramipexole dihydrochloride monohydrate treatment tended to be superior to bromocriptine treatment.

Restless legs syndrome.

The efficacy of pramipexole dihydrochloride monohydrate tablets in the treatment of Restless Legs Syndrome (RLS) was evaluated in a multinational drug development program consisting of four randomised, double-blind, placebo-controlled trials. This program included approximately 1000 patients with moderate to very severe primary (idiopathic) RLS; patients with RLS secondary to other conditions (e.g., pregnancy, renal failure and anaemia) were excluded. Patients were diagnosed with RLS based on standard criteria of the International RLS Study Group and were required to have a score of > 15 on the International RLS (IRLS) Rating Scale. The mean age was 55.1 years in the placebo group and 54.6 years in the pramipexole group. About three quarter of patients were below 65 years of age and about two thirds were female. The baseline mean IRLS Rating Scale score was 25.4 in placebo and 24.3 in the pramipexole-treated patients. The majority of patients in both treatment groups (55.7% [placebo] vs. 60.3% [pramipexole]) had a mean IRLS Rating Scale score between 21 and 30 indicative of a patient population with severe RLS. All patients were administered pramipexole dihydrochloride monohydrate (0.125 mg, 0.25 mg, 0.5 mg, or 0.75 mg) or placebo once daily 2-3 hours before going to bed.
The primary outcome measures in the two key RLS trials were:
1. IRLS Rating Scale - contains 10 items designed to assess the severity of sensory and motor symptoms, sleep disturbance, daytime somnolence, and impact on activities of daily living and mood associated with RLS. The range of scores is 0 to 40, with 0 being absence of RLS symptoms and 40 the most severe symptoms.
2. Clinical Global Impression-Improvement (CGI-I) assessment - a subset of CGI, which is designed to assess the severity of illness, clinical progress (global improvement), therapeutic effect, as well as side effects.
In Study 1, fixed doses of pramipexole were compared to placebo in a study of 12 weeks duration.
Patients treated with pramipexole dihydrochloride monohydrate (n = 254) had a starting dose of 0.125 mg/day and were titrated to one of the three active treatment groups (0.25, 0.5, 0.75 mg/day) in the first three weeks of the study. The mean improvement from baseline on the IRLS Rating Scale score and the percentage of CGI-I responders for each of the pramipexole treatment groups compared to placebo are summarised in Table 5. All treatment groups reached statistically significant superiority compared to placebo for both endpoints.
These results confirm the significant benefits of pramipexole (over placebo) observed in an earlier randomised, double-blind, placebo-controlled, flexible-dose study of 6 weeks duration. In this flexible-dose study, the decrease in the IRLS Rating Scale score for the pramipexole group (n = 224) (after 6 weeks of double-blind therapy) was statistically significant compared to the placebo group (adjusted mean change from baseline: -12.3 [pramipexole] vs. -5.7 [placebo]; adjusted mean difference to placebo [95% CI]: -6.6 [-8.6, -4.5], p = 0.0001). In addition, 62.9% of the pramipexole-treated patients reached a CGI-Global improvement of at least 'much improved', compared to only 32.5% patients in the placebo group (adjusted treatment difference to placebo [95% CI]: 30.4% [19.8, 41.2]). This difference was also statistically significant (p < 0.0001).
Study 2 demonstrated sustained efficacy of pramipexole for treatment of RLS over a period of nine months. RLS patients who responded to pramipexole dihydrochloride monohydrate treatment in a preceding 6-month open label treatment phase (7 on 0.125 mg, 44 on 0.25 mg, 47 on 0.5 mg, 49 on 0.75 mg) were randomised to receive either blinded active treatment at an individually optimised dose (n = 78) or placebo (n = 69) for 12 weeks. Responders were defined as having a CGI-I rating of "very much improved" or "much improved" compared to baseline and an IRLS score of 15 or below. The primary endpoint of this study was time to treatment failure based on a CGI-I score of "minimally worse" to "very much worse" and an IRLS Scale score above 15.
In patients who had responded to 6-month open label treatment with pramipexole, the administration of placebo led to a rapid decline in their overall conditions and worsening of their RLS symptoms (Figure 1). At the end of the 12-week observation period, 85% of patients treated with placebo had failed treatment, compared to 21% treated with blinded pramipexole; the difference between the treatment groups was highly statistically significant (p < 0.0001).
In a separate 3-week study, fixed doses of 0.125 mg, 0.25 mg, 0.5 mg, and 0.75 mg pramipexole dihydrochloride monohydrate were all shown to significantly reduce the number of periodic limb movements during sleep as measured by the Periodic Limb Movement during time in bed Index (PLMI) compared to placebo.
Upon initiation of treatment, 37% of 476 patients treated with pramipexole reported that they felt significantly better after one week of therapy, compared to 10% of 199 patients treated with placebo. During the long-term studies (without placebo control), the effect of pramipexole was maintained up to at least one year.
No differences in effectiveness based on age or gender were detected. There were too few non-Caucasian patients to evaluate the effect of race.

5.2 Pharmacokinetic Properties

Absorption.

Pramipexole is rapidly absorbed following oral administration. The absolute bioavailability of pramipexole is greater than 90%, indicating that it is well absorbed and undergoes little pre-systemic metabolism. Generally, concomitant administration with food does not affect the bioavailability of pramipexole.
Following administration of pramipexole tablets, maximum plasma concentration (Cmax) are reached in approximately 2 hours. Food does not affect the extent of pramipexole absorption, although the time of maximum plasma concentration (Tmax) is increased by about one hour when the drug is taken with a meal. Steady-state concentrations are achieved within 2 days of dosing.
Typical plasma concentration-time profiles after administration of pramipexole tablets three times daily, either every 8 hours (8-8-8) or in a 6-6-12 hour posology are given in Figure 2.

Distribution.

Pramipexole is extensively distributed, having a volume of distribution of about 500 L (coefficient of variation (CV) = 20%). It is about 15% bound to plasma proteins. Pramipexole distributes into red blood cells as indicated by an erythrocyte to plasma ratio of approximately two.

Metabolism.

Pramipexole displays linear pharmacokinetics over the clinical dosage range irrespective of dosage form. Peak to trough fluctuations of approximately 55% were seen with both the extended-release (ER) and immediate-release formulations and were highest with the fed ER formulation (mean 73%).
Pramipexole is metabolised in humans only to a small extent. No specific active metabolite has been identified in human plasma or urine.

Excretion.

Urinary excretion is the major route of pramipexole elimination, with 90% of a pramipexole dose recovered in urine, almost all as unchanged drug. Nonrenal routes may contribute to a small extent to pramipexole elimination, although no metabolites have been identified in plasma or urine. The renal clearance of pramipexole is approximately 400 mL/minute (CV = 25%), approximately three times higher than the glomerular filtration rate. Thus, pramipexole is secreted by the renal tubules, probably by the organic cation transport system. The terminal elimination half-life is about 8 hours in young healthy volunteers and about 12 hours in elderly volunteers (see Special populations).

Special populations.

Because therapy with pramipexole is initiated at a low dose and gradually titrated upward according to clinical tolerability to obtain the optimum therapeutic effect, adjustment of the initial dose based on gender, weight or age is not necessary. However, renal insufficiency, which can cause a large decrease in the ability to eliminate pramipexole, may necessitate dosage adjustment (see Section 4.2 Dose and Method of Administration).

Gender.

Pramipexole clearance is about 30% lower in women than in men, but most of this difference can be accounted for by differences in bodyweight. There is no difference in half-life between males and females.

Age.

Pramipexole clearance decreases with age as the half-life and clearance are about 40% longer and 30% lower, respectively, in elderly (aged 65 years or older) compared with young healthy volunteers (aged less than 40 years). This difference is most likely due to the well known reduction in renal function with age, since pramipexole clearance is correlated with renal function, as measured by creatinine clearance.

Parkinson's disease patients.

A cross study comparison of data suggests that the clearance of pramipexole may be reduced by about 30% in Parkinson's disease patients compared with healthy elderly volunteers. The reason for this difference appears to be reduced renal function in Parkinson's disease patients, which may be related to their poorer general health. The pharmacokinetics of pramipexole were comparable between early and advanced Parkinson's disease patients.

Restless legs syndrome (RLS) patients.

A cross-study comparison of data suggests that the pharmacokinetic profile of pramipexole administered once daily in RLS patients is generally consistent with the pharmacokinetic profile of pramipexole in healthy volunteers.

Paediatric.

The pharmacokinetics of pramipexole in the paediatric population have not been evaluated.

Hepatic insufficiency.

The influence of hepatic insufficiency on pramipexole pharmacokinetics has not been evaluated. Because approximately 90% of the recovered dose is excreted in the urine as unchanged drug, hepatic impairment would not be expected to have a significant effect on pramipexole elimination.

Renal insufficiency.

The clearance of pramipexole was about 75% lower in patients with severe renal impairment (creatinine clearance approximately 20 mL/minute) and about 60% lower in patients with moderate impairment (creatinine clearance approximately 40 mL/minute) compared with healthy volunteers. A lower starting and maintenance dose is recommended in these patients (see Section 4.2 Dose and Method of Administration). In patients with varying degrees of renal impairment, pramipexole clearance correlates well with creatinine clearance. Therefore, creatinine clearance can be used as a predictor of the extent of decrease in pramipexole clearance. Pramipexole clearance is extremely low in dialysis patients, as a negligible amount of pramipexole is removed by dialysis. Caution should be exercised when administering pramipexole to patients with renal disease.

5.3 Preclinical Safety Data

Genotoxicity.

Pramipexole was not mutagenic in in vitro assays for gene mutation, or cause chromosomal damage in in vitro and in vivo tests for clastogenic activity. Pramipexole was negative in an in vitro test for cell transformation.

Carcinogenicity.

Two-year carcinogenicity studies with pramipexole have been conducted in mice and rats. Pramipexole was administered in the diet to mice at doses of 0.3, 2 and 10 mg/kg/day (the plasma levels were at least 0.2, 1.2, and 5.7 times the observed Cmax in humans dosed 1.5 mg three times daily (tid)). Pramipexole was administered in the diet to rats at 0.3, 2 and 8 mg/kg/day (0.8, 5 and 20 times the highest clinical dose on a mg/m2 basis).
Increased incidences of testicular Leydig cell adenomas were found in all groups of treated male rats. In contrast to the findings in rats, examination of the testes from mice after two years of treatment did not exhibit evidence of a drug related increase in Leydig cell adenomas. These findings are of questionable significance in humans because of their high background incidence in rats, the absence of similar changes in mice treated with pramipexole for two years, and the probable involvement of endocrine mechanisms that are not relevant to humans.

6 Pharmaceutical Particulars

6.1 List of Excipients

Mannitol, pregelatinised maize starch, microcrystalline cellulose, povidone, purified talc and magnesium stearate.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf-life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 30°C. Protect from light.

6.5 Nature and Contents of Container

Simipex 0.125 mg tablets are available in blister packs of 30 tablets.
Simipex 0.25 mg tablets are available in blister packs of 100 tablets.
Simipex 1 mg tablets are available in blister packs of 100 tablets.
Simipex tablets 0.5 and 1.5 mg tablets are not currently marketed in Australia.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.

Pramipexole dihydrochloride monohydrate is a white to off white crystalline powder. Freely soluble in water, soluble in methanol, sparingly soluble to slightly soluble in ethanol (96%) and practically insoluble in methylene chloride.
The chemical name of pramipexole is (S)-2-amino-4,5,6,7-tetrahydro-6-propylamino-benzothiazole, [C10H17N3S], CAS registry number 104632-26-0, molecular weight 211.33.
Pramipexole tablets contain C10H17N3S.2HCl.H2O molecular weight 302.3, CAS registry number 191217-81-9 for which the Australian Approved Name is pramipexole dihydrochloride monohydrate.
The structural formula is:

CAS number.

CAS: 191217-81-9 (pramipexole dihydrochloride monohydrate).

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

Summary Table of Changes